This invention relates to foamable pharmaceutical and cosmetic compositions.
External topical administration is an important route for the administration of drugs in disease treatment. Many groups of drugs, including, for example, antibiotic, anti-fungal, anti-inflammatory, anesthetic, analgesic, antiallergic, corticosteroid, retinoid and anti-proliferative medications are preferably administered in hydrophobic media, namely ointment. However, ointments often form an impermeable barrier, so that metabolic products and excreta from the wounds to which they are applied are not easily removed or drained away. Furthermore, it is difficult for the active drug dissolved in the carrier to pass through the white petrolatum barrier layer into the wound tissue, so the efficacy of the drug is reduced. In addition, ointments and creams often do not create an environment for promoting respiration of the wound tissue and it is not favorable to the normal respiration of the skin. An additional disadvantage of petroleum jelly-based ointments and creams relates to the greasy feeling left following their topical application onto the skin, mucosal membranes and wounds.
Foams are considered a more convenient vehicle for topical delivery of active agents. There are several types of topical foams, including aqueous foams, such as commonly available shaving foams; hydroalcoholic foams, emulsion-based foams, comprising oil and water components, and oleaginous foams, which consist of high oil content. In skin therapy, oil containing foams are preferred, since oil contributes to skin protection and moisturization, which improve the therapeutic effect of the formulation.
Fatty acids and fatty alcohols counterparts and derivatives have been used in foamable formulations as foam adjuvants usually in low amounts of up to about 5% and may possibly have a therapeutic effect in the treatment of a variety of skin disorders and/or conditions. Some are waxy solids while others are liquid at room temperature and pressure. For example, in the case where the carbon backbone chain is 18C, stearic acid and stearyl alcohol are waxy solids whilst isostearic acid, oleic acid and oleyl alcohol are liquids. The significance of this difference in liquidity of molecules having the same or similar backbone chain on foamable compositions is investigated herein.
Jojoba oil has been used in foamable formulations usually in relatively low amounts of up to about 10% and may possibly have a therapeutic effect in the treatment of a variety of skin disorders and/or conditions.
Branched (i.e., non-straight chain) waxes like oleic acid are known to contribute to the skin penetration of an active agent.
Aldara, a commercially available topical cream containing imiquimod as active agent, uses 25% isostearic acid as a solubilizing agent.
Formulations comprising micronized imiquimod with fatty acids and fatty alcohols are known. The level of fatty acid in such formulations, however, is minimized to avoid idiosyncrasy. As such, these formulations are essentially free of isostearic acid. Moreover, such formulations are cream formulations and foam compositions of such formulations have not been specifically disclosed.
Emulsion based foam formulations comprising imiquimod and fatty acids in sufficient amount to solubilize imiquimod have been disclosed. These formulations are limited in the amount of isostearic acid that can be present in the formulation (typically 25% or less).
Aqueous foam compositions comprising partially neutralized fatty acids as organic solvents have been generally disclosed in the art. However, specific compositions containing additional components, such as polymers, surfactants, and liquid fatty acids have not been disclosed. The stability of such foams relies upon the presence of a component such as triethanolamine, as well as basic active components (such as imiquimod) to neutralize fatty acid and water foams.
Foam using very high amounts of anionic surfactants 20% to 95% with C10:0 (e.g., 1-decanol) fatty alcohol has been described in the art. The large amounts of surfactant result in a mesomorphic phase which solubilizes the propellant. The use of high levels of anionic surfactants and C10:0 fatty alcohol, which are irritants, renders these compositions unsuitable for use on the skin and eyes, and, in some cases, harmful, particularly in the eyes.
There remains an unmet need for improved, easy to use, vehicles and foam formulations, comprising wax, waxy substances, counterparts and derivatives thereof in preferably in substantial or higher concentrations which can effectively deliver and/or deposit various active agents into and onto the skin and/or other target sites and are relatively non-irritating and thus suitable for use by people having sensitive skin, body cavities and mucosal surfaces. Significantly there remains an unmet need for such vehicles and foam formulations that are substantially free from crystals. Accordingly, in some embodiments, the formulations described herein are free from crystals. In some embodiments, the formulations are free from an insoluble phase or, in some embodiments, free from insoluble matter. The presence of crystals indicates that one or more ingredients are not solubilized. In consequence amongst other things the formulation may be unstable, may be variable, may deliver unreliable amounts of active ingredients and may cause irritation and thus be unsuitable for therapeutic use. Additionally substantial crystal formation in a foamable formulation may interfere with foam release. In some embodiments, the formulations are free from crystals yet still include a suspension of solid matter or particles. In some embodiments, the solid matter or particles are not crystalline. Examples of such solid matter include, without limitation, microsponges, ground seed, metallic particles and active agents in particle form (e.g., benzyl peroxide).
There is a need for such vehicles and foam formulations in which there is a relatively low level of surfactants. Surfactants can be irritants particularly at higher levels. Repeated use of formulations with higher levels of surfactants on the skin can result in depletion of hydrophobic substances and dry skin.
High levels of surfactant can result in the formation of a mesomorphic phase. The mesomorphic phase can absorb propellant and may increase irritation, depletion of fats and dry skin. There is a need for such vehicles and foam formulations in which there is no mesomorphic phase